dbSNP rs784567: MAP3K12:c.-691C>T (chr12-53500681-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The XM_011538725.4(MAP3K12):c.-691C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,368 control chromosomes in the GnomAD database, including 11,792 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 11749 hom., cov: 31)

Exomes 𝑓: 0.43 ( 43 hom. )

Consequence

MAP3K12
XM_011538725.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0420

Publications

44 publications found

Variant links:

Genes affected

MAP3K12 (HGNC:6851): (mitogen-activated protein kinase kinase kinase 12) This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.[provided by RefSeq, Jul 2010]

MAP3K12 links:

ENSG00000270175 (HGNC:):

ENSG00000270175 links:

TARBP2 (HGNC:11569): (TARBP2 subunit of RISC loading complex) HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene binds between the bulge and the loop of the HIV-1 TAR RNA regulatory element and activates HIV-1 gene expression in synergy with the viral Tat protein. Alternative splicing results in multiple transcript variants encoding different isoforms. This gene also has a pseudogene. [provided by RefSeq, Jul 2008]

TARBP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
MAP3K12	XM_011538725.4 link	c.-691C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	XP_011537027.1	Q12852-2
MAP3K12	XM_011538725.4 link	c.-691C>T	5_prime_UTR_variant	Exon 1 of 14	XP_011537027.1	Q12852-2
TARBP2	NM_004178.5 link	c.-326G>A	upstream_gene_variant		NP_004169.3	Q15633-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ENSG00000270175	ENST00000602306.2 link	n.895C>T	non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000293778	ENST00000718934.1 link	n.570G>A	non_coding_transcript_exon_variant	Exon 2 of 2
TARBP2	ENST00000550147.5 link	n.-728G>A	upstream_gene_variant		1	ENSP00000450320.1	F8VP94

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52636

AN:

151844

Hom.:

11748

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0959

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.305

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.00984

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.483

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.503

Gnomad OTH

AF:

0.381

GnomAD4 exome

AF:

0.431

AC:

175

AN:

406

Hom.:

Cov.:

AF XY:

0.439

AC XY:

144

AN XY:

328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.421

AC:

AN:

178

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.457

AC:

AN:

188

Other (OTH)

AF:

0.438

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.346

AC:

52638

AN:

151962

Hom.:

11749

Cov.:

AF XY:

0.343

AC XY:

25471

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.0957

AC:

3970

AN:

41496

American (AMR)

AF:

0.304

AC:

4638

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.416

AC:

1442

AN:

3468

East Asian (EAS)

AF:

0.00986

AC:

AN:

5172

South Asian (SAS)

AF:

0.385

AC:

1858

AN:

4820

European-Finnish (FIN)

AF:

0.483

AC:

5095

AN:

10542

Middle Eastern (MID)

AF:

0.486

AC:

143

AN:

294

European-Non Finnish (NFE)

AF:

0.503

AC:

34154

AN:

67912

Other (OTH)

AF:

0.387

AC:

815

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1480

2960

4441

5921

7401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.430

Hom.:

40712

Bravo

AF:

0.321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.3

(source)

DANN

Benign

0.73

PhyloP100

-0.042

PromoterAI

-0.0074

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over